[CIS PIDD] [cis-pidd] Conflicting complement test results

[Keller, Michael]

Thanks very much for the comments!   I will repost when we have an update.

Mike

-------------------------

Michael D. Keller MD

Division of Allergy / Immunology

Children's National Health System

111 Michigan Ave NW, Room 1W-314B

Washington, DC 20010

Clinic: 202.476.3016

Office: 202.476.5843

Fax: 202.476.2280

www.childrensnational.org


________________________________________
From: Verbsky, James [jverbsky at mcw.edu]
Sent: Tuesday, April 22, 2014 10:48 AM
To: CIS-PIDD
Subject: RE:[cis-pidd] Conflicting complement test results

Mike...ran this by John Atkinson...here are his thoughts

Best

James

James,
I think I can solve this one for you and I may
have seen it before! Comments and Suggestions
1. Patient most likely has C2
deficiency - no C2 antigen and no C2 function and a compatible clinical
history.
2. CH50 discrepancy may be explained
as follows: If the lab doing the CH50
assay just puts more antibody on the SRBCs, then the C2 bypass pathway kicks
in. For example, I have a patient with C2 deficiency who I have followed for
nearly 40 years. On one of many CH50 assays, it came back from Barnes Hospital
lab as being ~50% normal. We did the assay in my lab and it was zero (as
always). We went to the lab to review the assay and it soon became apparent
that ~10 times more antibody had been incorrectly used to sensitize the RBCs.
The lab at Barnes Hospital had misinterpreted an antibody titration curve. It
didn't make a difference in titer unless you were C2 deficient (see attached
paper).
3. The other and more inexplicable
result is a C2 Ag level of <10 and then 20.1 a year later. The C2 functional
test was zero both times. I can't explain this. If the patient was producing a
non-functional C2, then this would make sense. However, the C2 Ag was absent in
the first assay. My prediction is that one of these two represent a lab error.
4. A less likely possibility is that
the patient has an autoantibody to C2 which was blocking and premature clearing
the C2 protein initially but now is just blocking its function. Doesn't make
much sense and rather complicated.
5. Sequence C2 gene and do HLA
typing. Most patients (~90%) have C2 deficiency on a certain HLA haplotype so
you could also perform HLA-typing. The other 10% though are on a variety of HLA
haplotypes.
6. Repeat C2 Ag and function.
Publications:
1. Steuer, K.L.K., Sloan, L.B., Oglesby, T.J., Farries, T.C.,
Nickells, M.W., Densen, P., Harley, J.B. and Atkinson, J.P.: Lysis of sensitized sheep erythrocytes in
human sera deficient in the second component of complement. J. Immunol.
143:2256-2261, 1989.
2. Farries, T.C., Knutzen-Steuer, K.L., and Atkinson, J.P.: The
mechanism of activation of the alternative pathway of complement by cell-bound
C4b. Mol. Immunol. 27:1155-1161,
1990.

All the best,
John
-----Original Message-----
From: Keller, Michael [mailto:MKeller at childrensnational.org]
Sent: Monday, April 21, 2014 1:50 PM
To: CIS-PIDD
Subject: [cis-pidd] Conflicting complement test results

Greetings everyone,

We have an odd case, and would be most grateful for everyone's thoughts.

Our patient is a 4-year-old boy with history of mastoiditis complicated by an epidural brain abscess and sinus venous thrombosis at 22 months of age.   Surgical cultures grew streptococcus pneumonia.   He had recurrent sinopulmonary infections, beginning in the second year of life, with multiple ear infections prior to the mastoiditis episode.

He was a full-term infant, born to non-consanguinous parents of Hispanic ancestry.
There is no family history of immune disorders, autoimmune/rheumatologic disorders, early malignancies, or unexplained deaths or miscarriages.

He has had all vaccinations without issue to date.

His workup immediately following the epidural abscess was as follows:

IgG/IgA/IgM normal
S. pneumonia titers protective to 8/14 tested Hib titer protective
C2 level: <10 (normal 22-39 mcg/ml)
C3 149
C4 19
C1q: 1789 units/ml
CH50 initially <12 (confirmed on repeat blood draw)
C2 function: 0

He was started on PenVK prophylaxis after these findings.

Oddly, when I met him roughly a year later, his labs were as follows:

CH50: 217 (176-382)
AH50: 74 (normal 77-159)
Properdin level: 34.6 (22.3-67.6)
C2 level: 20.1
C2 function: 0
IgG 851 mg/dl , IgA 57, IgM 131
The commercial TLR assay was normal.
Lymphocyte flow cytometry was essentially normal: abs CD3 3451, CD3/4: 1906, CD3/8: 1082, CD19 1391, CD16/56(CD3-): 258, CD45RA:CD45RO ratio (within CD4+ Tcells) of 4:1.
S. pneumonia IgG titers were protective to 6/14 tested serotypes N meningitides IgG titers were 4/4 protective VZV, Measles IgG were both protective

He's doing fairly on antibiotic prophylaxis, and his only other medical issues are moderate asthma which improved with flovent use and possible developing ADHD.  He is still on PenVK, and we are boosting him with pneumonax given these results.

I'm a bit puzzled by the conflicting data between the C2 function and the CH50/AH50.    It doesn't make much sense to have relatively intact classical complement activity with absent C2 function.

Thanks in advance!

Mike

---------------
Michael D. Keller MD
Division of Allergy / Immunology
Children's National Health System
111 Michigan Ave NW, Room 1W-314B
Washington, DC 20010
Clinic: 202.476.3016
Office: 202.476.5843
Fax: 202.476.2280
www.childrensnational.org

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